We have explored new cycloaddition chemistry of the anion of trimethylsilyldiazoalkane with
a,b-unsaturated cyclic ketones as well as ketones with
tethered alkenes and alkynes. This chemistry has been expanded beyond the a,b-unsaturated cyclic ketones. In addition
to the previously reported results, we have developed a general protocol to
form pyrazolines from a,b-unsaturated
esters. Under optimized conditions, very high diastereoselectivity of products
could be achieved. The high diastereoselectivity is probably is the consequence
of the chelate formation that can discriminate the two diastereotopic faces
effectively for the addition of the incoming dipole (Table 1).

a-Amino ketone is a
structural motif that exists in numerous natural products and pharmaceuticals.
Conceptually, this functional group can be installed by a-amination, a process wherein a
nitrogen-based electrophile reacts with an enolate nucleophile derived from
carbonyl compounds. Many a-amination methods have
been developed, yet most of these methods share a common problem dealing with
removal of the extra functionality on the nitrogen after the C–N bond
formation. Therefore, inventing new methods that can introduce a free amino
group would have a significant merit over the existing a-amination methods.

Toward
this goal, we envisioned the addition of lithium trimethylsilyldiazomethane to a,b-unsaturated ketones esters followed by
mild N–N bond cleavage would lead to an efficient synthesis of a-amino
ketone and ester. We have explored the N–N bond cleavage and postulated that the presence of a trimethylsilyl group on our
pyrazolines would facilitate both an oxidative or proteolytic N–N bond
cleavage (Table 2). We hypothesized that under oxidative conditions, a single
electron transfer from sp3-hybridized
nitrogen to an oxidant would generate a radical cation intermediate, which then
will submit to an attack by a nucleophile at the trimethylsilyl group to induce
a simultaneous C–SiMe3 and N–N bond cleavage, providing
a-amino ketones or esters. In the other scenario, good to excellent yield of N–N
bond cleavage product were obtained.

On the basis of
these concatenated transformations involving pyrazoline formation and its
N–N bond cleavage, we are able to construct molecular structures that contain
a-amino quaternary centers. We applied the prowess of this transformation to
the total synthesis natural products that have these structural characteristics
such as amathaspiramides as shown in the (Scheme 1). Via standard
transformations, the dipolar addition substrate was synthesized and the
pyrazoline was obtained as expected. Cleavage of the N–N bond under the
developed conditions provided the pivotal intermediate in a very short
synthetic sequence. The elaboration of the nitrile functionality to the
corresponding diimide followed by regioselective reduction provided
amathaspiramide C, which will be transformed to amathaspiramide C under the
known conditions.